tbuckley/cabot-search huggingface dataset:
3D Bioprinted Silk‐Based In Vitro Osteochondral Model for Osteoarthritis Therapeutics
Authors: Yogendra Pratap Singh, Joseph Christakiran Moses, Ashutosh Bandyopadhyay, Biman B. Mandal
Journal: Advanced Healthcare Materials (2022)

3D bioprinting of osteochondral tissue offers unique opportunities for enabling precise pharmacological interventions in osteoarthritis (OA). The current study investigates the screening potential of anti-inflammatory drugs using bioprinted inflamed human osteochondral units. The biomimetic hierarchical geometry is bioprinted using silk-based bioinks encapsulating pre-differentiated stem cells, creating an in vitro model. Inflammation is stimulated in the model, using tumor necrosis factor-alpha and Interleukin-1 beta pro-inflammatory cytokines. The resultant degeneration, akin to OA, is flagged by key markers like sulfated glycosaminoglycan, collagen, alkaline phosphatase, and downregulation of osteochondral transcript levels. In the next step, the screening of anti-inflammatory drugs is validated using celecoxib and rhein. Consequently, in the inflamed constructs, the initial upregulation of the key inflammatory mediators (nitric oxide, Prostaglandin E2), is subsequently downregulated, post-drug treatment. In addition, catabolic markers (matrix metalloproteinases and aggrecanase-1), indicative of hypertrophic and apoptosing chondrocytes, are significantly downregulated in the treatment groups; while the transcript and protein levels required for osteochondral health are attenuated. Therefore, the in vitro model mimicks the inflammation in the early stages of OA, and corroborates a potential high-throughput platform for screening novel anti-inflammatory drugs in OA therapeutics.
Measuring the great objective: Have we transferred the increase in overall survival in stage IV non-small cell lung cancer from clinical trials to clinical practice?
Authors: Juan Cristobal Sanchez, Beatriz Nuñez García, Mariola Blanco, Virginia Calvo, Blanca Cantos Sanchez de Ibarguren, Miriam Mendez, Ramon Aguado, Arturo Jose Ramos-Vegue, Ana Royuela, Mariano Provencio-Pulla
Journal: Journal of Clinical Oncology (2022)

e18734 Background: In the last five years, different immunotherapy (IO) clinical trials have improved overall survival (OS) for stage IV non-small cell lung cancer (NSCLC) without driver mutation. However, it is necessary to check whether outcomes of clinical trials are reproduced in the general population, the true objective of any scientific advance. Methods: We conducted a retrospective observational study selecting all patients with stage IV NSCLC without driver mutation treated in the Medical Oncology Department at Puerta de Hierro University Hospital between 2016 and 2019. Data cut off was June 30, 2021. Our goal was to evaluate treatment changes for NSCLC in clinical practice in our institution with OS in the real-world as the main outcome, in addition to assessing quality of care. Results: Between 2016 and 2019, 317 patients with stage IV NSCLC were diagnosed, 260 without driver mutation and 189 of them received systemic treatment. We observed a higher proportion of stage IVB patients in 2018 and 2019 compared to 2016 and 2017. A progressive greater use of IO was observed, except for a small decrease in 2019 compared to 2018. At the date of analysis, 77.8% of patients had died. With a median follow-up of 40.8 months, we observed a gradual increase in OS, with medians of 12.3, 13.6, and 18.9 months for patients diagnosed in 2016, 2017, and 2018, respectively, with a decrease to 10.4 months for patients diagnosed in 2019. Survival rates over time show the same trend. IO (any line) was significantly associated with a reduced risk of death: HR 0.35 (95% CI: 0.23 - 0.58) in multivariate analysis. The deterioration of the results of the patients diagnosed in 2019 is manifested in the median survival and in the survival rates at different points from 6 months onwards, which should correspond to the excess mortality in the year 2020 in our studied population. Conclusions: Our study shows that IO reduced risk of death: HR 0.35 (95% CI: 0.23 - 0.58) in stage IV NSCLC, observing an increase in overall survival from a median of 12.3 to 18.9 months for patients diagnosed in 2016 and 2018, suggesting that the progressive use of IO for NSCLC in the years 2016, 2017 and 2018 has transferred the benefit observed in clinical trials to the general population. The deterioration of outcomes for patients diagnosed in 2019, with a median OS of 10.4 months and decreased survival at 6, 12 and 18 months, could suggest the negative impact and excess mortality in the pandemic year 2020.[Table: see text]
First ever reported case of continuous spinal anesthesia da Vinci robotic partial nephrectomy
Authors: P. Gontero, M. Oderda, G. Calleris, M. Allasia, M. Agnello, P. Rampa, F. Soria, F. Lavagno, S. Mazzoli, M. De Bellis, F. Vitiello, L. Brazzi, R. Balagna, F. Gobbi
Journal: European Urology (2022)
Clinical and genomic characterization of <i>ERBB2</i>-altered gallbladder cancer.
Authors: Sebastian Mondaca, Nikolaus Schultz, Juan Carlos Roa, Henry S. Walch, Santiago Sepulveda, James J. Harding, Amin Yaqubie, Patricia Garcia, Gloria Aguayo, Bruno Nervi, Bob T. Li, Ghassan K. Abou-Alfa
Journal: Journal of Clinical Oncology (2022)

4114 Background: Gallbladder cancer (GBC) is a molecularly distinct entity among biliary tract tumors. ERBB2 amplification and mutation have been described in GBC, however, clinical and genomic characterization of the ERBB2-altered subgroup has been limited. Methods: Patients with GBC treated at Memorial Sloan Kettering and Pontificia Universidad Católica de Chile with genomic tumor profiling between 2014 and 2021 were included. Clinical information was retrieved from electronic medical records. Categorical data were analyzed by Fisher exact test and time-to-event data were analyzed by Cox proportional hazards models. Results: During the study period 260 GBC patients underwent genomic profiling. The prevalence of ERBB2 alterations was 14% including 8% with ERBB2 gene amplification, 4.2% with ERBB2 mutation, 1.5% with concurrent amplification and mutation and 0.4% with ERBB2 fusion. There was no age difference between GBC patients with and without ERBB2 alterations (63.6 vs. 65.4; p = 0.36) and in both subgroups there was a majority of female patients (75% vs. 84%; p = 0.44). Patients with ERBB2-altered tumors had a different genomic profile with lower concurrent KRAS alterations (2% vs. 12%; p = 0.14) and higher prevalence of TP53 alterations (81% vs. 59%; p = 0.01). There was no difference in the prevalence of PIK3CA mutations (13% vs. 9%; p = 0.38). GBC patients with ERBB2 alterations had a longer overall survival (22.3 vs. 12.1 months; HR 0.54 95% CI 0.3 to 0.98). Conclusions: ERBB2 amplification and mutation are the most frequent potentially targetable alterations in GBC (14%). ERBB2-driven GBC has higher concurrent alterations of TP53, while KRAS alterations appear to be less frequent. While no particular clinical feature was associated with this subgroup, overall survival was longer.
PD-1 blockade combined chemotherapy and bevacizumab in DNA mismatch repair-proficient/microsatellite stable colorectal liver metastases.
Authors: Qianqian Men, Jun Huang, Yinghua Duan, Fengyun Pei, Wan He, Huabin Hu, Yandong Zhao, Lishuo Shi, Peiyi Xie, GuangJian Liu, Meijin Huang
Journal: Journal of Clinical Oncology (2022)

e15547 Background: Although PD-1 blockade has been recommended as the first line treatment in DNA mismatch repair-deficient/microsatellite instability-high (dMMR/MSI-H) metastatic colorectal cancer (mCRC), it is worthwhile to investigate whether mCRC with DNA mismatch repair-proficient/microsatellite stable(pMMR/MSS) tumors benefit from a combination treatment with PD-1 blockade. Methods: In this cohort, ten patients with pMMR/MSS colorectal liver metastases (CRLM) treated in the 6 th Affiliated Hospital of Sun Yat-sen University were enrolled. All the patients were exploratively treated with at least four doses of PD-1 monoclonal antibody combined with chemotherapy and bevacizumab as neoadjuvant/adjuvant therapy. The aim of the study was to evaluate the short-term efficacy and safety of this combined strategy. Results: All the 10 patients were confirmed pMMR/MSS by IHC or next generation sequencing (NGS). Eight of the 10 patients accepted the combined therapies before primary tumor resections, disease control rate (DCR) was 100% (8/8) and objective response rate (ORR) was 62.5% (5/8). The ORR of liver metastases was 70% (7/10) after this treatment. Pathologic complete response (pCR) was achieved in one patient’s primary tumor and was also achieved in another patient’s hepatic lesion. Four patients underwent simultaneous resection of primary tumor and liver metastases. Nine patients underwent microwave ablation for liver metastases. Five patients were assessed no evidence of disease (NED) with a median progress-free survival (PFS) of 5.0 (4.2-9.9) months after multimodality treatments for both primary and metastatic lesions. No immunotherapeutic associated sever adverse event (SAE) or operational complications were found in this cohort. Conclusions: PD-1 blockade combined chemotherapy and bevacizumab was safe and effective for patients with pMMR/MSS CRLM, which might lead to better tumor regression as well as more chances of NED. Further clinical phase II studies of evaluation of long-term efficacy of this combined strategy was needed.
Atezolizumab plus bevacizumab versus lenvatinib or sorafenib in non-viral unresectable hepatocellular carcinoma: An international study.
Authors: Andrea Casadei-Gardini, Margherita Rimini, Lorenza Rimassa, Valentina Burgio, Masatoshi Kudo, Toshifumi Tada, Shigeo Shimose, Goki Suda, Changhoon Yoo, Jaekyng Cheon, David J. James Pinato, Mario Scartozzi, Stefano Cascinu
Journal: Journal of Clinical Oncology (2022)

4069 Background: Recently, several evidences have suggested that patients with a no-viral hepatocellular carcinoma (HCC) might be less responsive to immunotherapy and more response to Lenvatinib. Methods: The study population derived from prospectively collected retrospectively analyzed data of patients treated with atezolizumab plus bevacizumab (AB) or lenvatinib (L) or sorafenib (S) as first-line treatment for advanced HCC or intermediate HCC deemed not eligible for loco-regional therapies. The overall cohort included Western and Eastern patient populations from 36 centers located in 4 countries(Italy, Japan, Republic of Korea, and United Kingdom) undergoing treatment with L or AB or with S. The primary endpoint was OS of AB versus L; the secondary endpoints were OS of AB versus S. Results: 569 patients received L, 190 patients received AB and 210 received S. In the whole population OS was 17.8 months (95%CI:15.8-43.8) for patients receiving L, and 12.1 months(95%CI:11.1-16.8)for patients treated with AB (HR 0.71; 95% CI:0.50-1.06; p=0.1028); multivariate analysis for imbalance patients characteristic highlighted that L is an independent prognostic factor for OS (HR 0.65; 95% CI:0.44-0.95; p=0.0268), compared AB. In the population affected by NASH/NAFLD, 254 patients were treated with L and 82 patients were treated with AB. OS was 21.2 months (95% CI:18.4-30.6) for patients receiving L, and 12.2 months (95% CI:10.0-16.8) for patients treated with AB (HR 0.46; 95% CI:0.25-0.88; p = 0.0181); multivariate analysis for imbalance patients characteristic highlighted that L is an independent prognostic factor for OS (HR 0.46; 95% CI:0.26-0.84; p=0.031),compared AB. In the cohort of no viral and no NASH/NAFLD patients, no statistically significant differences were reported in terms of OS between patients treated with L versus AB. All these results were confirmed following propensity score matching analysis. By comparing patients receiving AB versus S, no significant differences were found in terms of OS in the whole population, in the NASH/NAFLD population and in no viral/no NASH/NAFLD population. Conclusions: The present analysis conducted on a large number of non-viral HCC patients showed for the first time a significant survival benefit from lenvatinib over atezolizumab plus bevacizumab, in particular in patients with NAFLD/NASH-related HCC.
HGG-33. Prognostic factors of H3K27M histone-mutant diffuse midline gliomas in patients ≤18yrs
Authors: Qingjun Hu, Mingyao Lai, Juan Li, Linbo Cai
Journal: Neuro-Oncology (2022)

Abstract OBJECTIVE：Diffuse midline gliomas associated with high malignancy and poor prognosis. The primary treatment modalities include surgery, radiotherapy and chemotherapy. The purpose of this study was to investigate the prognostic factors of diffuse intracranial midline glioma. METHODS: A retrospective analysis was performed on 44 cases younger than 18 yrs of H3K27M histone-mutant diffuse midline gliomas diagnosed in Guangdong Sanjiu Brain Hospital from November 2017 to November 2021. The median age was 9 years (range:3-18), including 24 males and 20 females, lesions located in thalamus were 9, while in brain stem were 35. Treatment methods: 35 cases received radiotherapy, 9 cases did not. Among the patients who received RT, 26 cases with concurrent chemoradiotherapy + adjuvant chemotherapy, 8 cases with concurrent chemoradiotherapy only, and 1 case only with radiotherapy. Kaplan-meier method was used to calculate overall survival (OS), and log-rank test was used to test. P &amp;lt; 0.05 was considered statistically significant. RESULTS: By January 27, 2022, 13 cases survived, 25 cases died, and 6 cases were lost to follow-up. The median survival time of 44 patients was 6.95 months (range：1-23.5 months). The median survival was 8.4 months in the radiotherapy group vs 3.7 months in the non-radiotherapy group (P＜0.001); The median survival time of radiotherapy without adjuvant chemotherapy vs radiotherapy with adjuvant chemotherapy was 6.2 months vs 9.35 months (P=0.479). CONCLUSION: Radiotherapy can prolong the survival time of diffuse midline glioma in children with H3K27M histone mutant but no survival benefit was observed in patients with concurrent chemotherapy.
Temporal trends of lung cancer burden in India in comparison to global burden from 1990 to 2019: An observation analysis.
Authors: Chinmay Jani, Ruchi Tusharkumar Jani, Jonathan Kurman, Harpreet Singh
Journal: Journal of Clinical Oncology (2022)

e21081 Background: Lung cancer is the leading cause of cancer-related deaths worldwide and remains a significant health concern globally. There is limited understanding of the lung cancer epidemiology trends in India. This study compares lung cancer incidence, disability-adjusted life years (DALYs), and mortality in the Indian population with the global burden. Methods: The lung cancer incidence, DALYs, and mortality data were analyzed for males and females from 1990-2019 using the Global Burden of Disease (GBD) database. GBD is an open-source data repository managed by the Institute for Health Metrics and Evaluation research center, University of Washington. International Classification of Diseases (ICD) code C34 were used for data extraction. Temporal trends in lung cancer were evaluated using descriptive statistics. Results: India had a lower lung cancer-related disease burden than the global population. Incidence trends: In India, lung cancer age-standardized incidence rates (ASIRs) increased from 6.62/100,000 in 1990 to 7.7/100,00 in 2019. ASIRs increased from 10.36 to 11.16 in males and 2.68 to 4.49 in females. In contrast, overall and male ASIRs decreased globally from 28.39 to 27.66 and 46.22 to 40.44, respectively. But global lung cancer incidence in females increased from 13.77 to 16.83, mirroring the trends in the Indian female population. DALYs trends: In India, DALYs increased uniformly from 1990 to 2019. The overall DALYs (including males and females) increased from 166.66 to 190.16. In males, DALYs increase from 258.05 to 271.30, and in females DALYs increase from 68.80 to 112.90. Similarly, at the global level, DALYs in females increased from 311.7 to 327.57. However, overall and male’s global DALYs improved from 657.97 to 551.58 and 1053.25 to 802.86, respectively. Mortality trends: In the Indian population, there was only a slight overall increase in age-standardized mortality rates (ASMRs) from 7.04 to 8.06. A similar slight increase in mortality rates was observed in males (11.04 to 11.73). However, in females, there was a substantial increase from 2.85 to 4.70. In contrast, overall and male ASMRs decreased globally from 27.39 to 25.18 and 45.08 to 37.38, respectively. Similar females’ mortality trends in India, globally, females ASMRs increased from 13.04 to 14.96. Conclusions: Our study reports a lower lung cancer-associated health burden in the Indian population. However, there is an increase in the incidence, DALYs, and mortality in both males and females in the Indian population from 1990 to 2019. Similar worsening trends are observed in females at the global level. In contrast, there is a hint towards improvement in the incidence, DALYs, and mortality at the global level in general, primarily due to improvement in males’ disease burden. There is also a persistent gap in males and females epidemiology, where males have a higher lung cancer burden than females.
Targeting <i>HER2 </i>mutation–positive advanced biliary tract cancers with neratinib: Final results from the phase 2 SUMMIT basket trial.
Authors: James J. Harding, Sarina Anne Piha-Paul, Ronak H. Shah, James M. Cleary, David I. Quinn, Irene Brana, Victor Moreno, Mitesh J. Borad, Sherene Loi, Iben Spanggaard, James M. Ford, Daniel DiPrimeo, Michael F. Berger, Lisa DeFazio Eli, Funda Meric-Bernstam, David B. Solit, Ghassan K. Abou-Alfa
Journal: Journal of Clinical Oncology (2022)

4079 Background: HER2 mutations are infrequent genomic events in biliary tract cancers (BTCs) and are associated with poor overall survival (OS) in patients with metastatic disease. HER2 overexpression is associated with an increased risk of disease recurrence in patients with resected BTC. There is limited data on targeting HER2 in BTC harboring activating somatic HER2 mutations. Neratinib, an irreversible, pan-HER, oral tyrosine kinase inhibitor, interferes with constitutive receptor kinase activation and has demonstrated activity in several HER2-mutant solid tumors. Methods: SUMMIT is an open-label, single-arm, multi-cohort, phase 2, ‘basket’ trial of neratinib in patients with solid tumors harboring oncogenic HER2 somatic mutations. The primary objective of the BTC cohort was to estimate objective response rate (ORR). Secondary objectives were clinical benefit rate (CBR), progression-free survival (PFS), OS, response duration, safety, and tolerability. Retrospective central confirmation of locally reported HER2 mutation (next-generation sequencing on archival or fresh tumor tissue using MSK-IMPACT or in cfDNA extracted from plasma by MSK-ACCESS) and association with outcome was an exploratory endpoint. This trial is registered with ClinicalTrials.gov (NCT01953926). Results: 25 treatment-refractory patients with metastatic BTC were enrolled (11 cholangiocarcinoma, 10 gallbladder, 4 ampullary cancers). ORR was 16% (95% CI 4.5–36.1%) and CBR was 28% (95% CI 12.1–49.4%). Median PFS and OS were 2.8 (95% CI 1.1–3.7) and 5.4 (95% CI 3.7–11.7) months, respectively. Median PFS for the gallbladder, cholangiocarcinoma and ampulla cohorts was 3.7 (95% CI 0.8–6.4), 1.4 (95% CI 0.5–9.1), and 1.1 (95% CI 1.1–3.8) months, respectively. Corresponding median OS values in these cohorts were 9.8 (95% CI 2.4–NE), 5.4 (95% CI 0.8–16.2), and 5.0 (95% CI 3.7–10.2) months, respectively. Central mutation confirmation was feasible for 23 of 25 patients; 22 were concordant with enrolment assays. The most common HER2 mutations were S310F (n = 11; 48%) and V777L (n = 4; 17%). Exploratory analyses suggested worse outcomes for HER2-mutant tumors with co-occurring oncogenic TP53 and CDKN2A alterations. Loss of amplified HER2 S310F and acquisition of multiple previously undetected oncogenic co-mutations were identified at progression in one of four responders. Diarrhea (56% any grade) was the most common toxicity. Conclusions: Neratinib is tolerable with modest antitumor activity in patients with BTC harboring HER2 mutations. Although the primary endpoint was met, future studies should evaluate rational combinations to augment and/or prolong responses. Clinical trial information: NCT01953926.
INSP-03. Neuronal regulation of glioma progression
Authors: Michelle Monje
Journal: Neuro-Oncology (2022)

Abstract The nervous system regulates stem and precursor cell behavior across a range of tissues. In the central nervous system, neuronal activity is a critical regulator of development and plasticity. Activity-dependent proliferation of healthy glial progenitors, oligodendrocyte precursor cells (OPCs), and the consequent generation of new oligodendrocytes contributes to adaptive myelination. This plasticity of myelin tunes neural circuit function and contributes to healthy cognition. The robust mitogenic effect of neuronal activity on normal oligodendroglial precursor cells, a putative cellular origin for many forms of glioma, suggests that dysregulated or “hijacked” mechanisms of myelin plasticity might similarly promote malignant cell proliferation in this devastating group of brain cancers. Indeed, neuronal activity regulates initiation and promotes progression of gliomas in preclinical models. Crucial mechanisms mediating activity-regulated glioma progression include secretion of BDNF and the synaptic protein neuroligin-3 (NLGN3). NLGN3 induces multiple oncogenic signaling pathways in the cancer cell, and also promotes glutamatergic synapse formation between neurons and glioma cells. This synaptic and electrical integration of glioma into neural circuits is central to tumor progression in preclinical models. NLGN3 is necessary for the growth of gliomas in a range of preclinical models, and therapeutic targeting of NLGN3 is presently under clinical investigation. Thus, neuron-glial interactions not only modulate neural circuit structure and function in the healthy brain, but paracrine and synaptic neuron-glioma interactions also play important roles in the pathogenesis of glial cancers. The mechanistic parallels between normal and malignant neuron-glial interactions underscores the extent to which mechanisms of neurodevelopment and plasticity are subverted by malignant gliomas, and the importance of understanding the neuroscience of cancer.
Capio TM Slim Suture Device x Tissue Anchoring System has different results in treatment of advanced pelvic organ prolapse? Prospective and Randomized study: Partial Results with 12 months follow-up
Authors: R.J. Moreira, R.R. Richetti, S.P. Vidotti, S. Hwang, A.P. Mendonça, A. Machado, R.A.H. Mendonça, L.G.M. Toledo
Journal: European Urology (2022)